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Nitrosated and nitrosylated compounds, compositions and methods use

a technology of nitrosated and nitrosylated compounds, applied in the field of new materials, can solve the problems of no material developed that matches the blood-compatible surface of the endothelium, no synthetic material created that is free of this effect, and the use of anticoagulant and platelet inhibition agents has been less than satisfactory in preventing adverse effects

Inactive Publication Date: 2006-01-12
NICOX SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The invention describes novel nitrosated and/or nitrosylated compounds of the invention and methods for treating cardiovascular diseases and disorders by administering one or more nitrosated and/or nitrosylated compounds of the inven

Problems solved by technology

No material has, however, been developed that matches the blood-compatible surface of the endothelium.
Despite considerable efforts to develop nonthrombogenic materials, no synthetic material has been created that is free from this effect.
In addition, the use of anticoagulant and platelet inhibition agents has been less than satisfactory in preventing adverse consequences resulting from the interaction between blood and artificial surfaces.

Method used

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  • Nitrosated and nitrosylated compounds, compositions and methods use
  • Nitrosated and nitrosylated compounds, compositions and methods use
  • Nitrosated and nitrosylated compounds, compositions and methods use

Examples

Experimental program
Comparison scheme
Effect test

example 1

(N-(2-Methyl-2-(nitrosothio)propyl)carbamoyl)methyl 2-((2E)-3-(3,4-dimethoxyphenyl)prop-2-enoylamino)benzoate

[0467]

1a. 2-((2E)-3-(3,4-Dimethoxyphenyl)prop-2-enoylamino)benzoic acid

[0468] The title compound was prepared from 3,4-dimethoxycinnamyl chloride and anthranilic acid according to the procedure in U.S. Pat. No. 3,940,422. 1H NMR (300 MHz, CDCl3 / d6-DMSO) δ 11.62 (s, 1H), 8.84 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.66 (d, J=15.5 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.05-7.18 (m, 3H), 6.89 (d, J=8 Hz, 1H), 6.50 (d, J=15.5 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H). Mass spectrum (API-TIS) m / z 328 (MH+).

1b. tert-Butyl 2-(2-((2E)-3-(3,4-dimethoxyphenyl)prop-2-enoylamino)phenyl carbonyloxy)acetate

[0469] The product of Example 1a (3.85 g, 11.8 mmol), potassium carbonate (1.62 g, 11.8 mmol) and tert-butyl bromoacetate (1.9 mL, 2.52 g, 13 mmol) in DMF (60 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with a large volume of EtOAc, washed several times...

example 2

3-Methyl-3-(nitrosothio)butyl 2-(2-((2E)-3-(3,4-dimethoxyphenyl)prop-2-enoylamino)phenylcarbonyloxy)acetate

[0473]

2a. 3-Methyl-3(2,4,6-trimethoxyphenylmethylthio)butan-1-ol

[0474] To a solution of 3-methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric acid (prepared as described by Lin et al., Tet. Letts., 43: 4531-4533 (2002), (5 g, 16 mmol) in THF (50 mL) was added carefully, in portions, lithium aluminium hydride (0.9 g, 23 mmol). The reaction mixture was refluxed for 4 hours, cooled to room temperature, quenched with water and extracted with EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined extracts were washed with satd sodium bicarbonate, satd. NaCl, dried with Na2SO4, filtered and evaporated to give the title compound (4.5 g, 90% yield). Mp 69-72° C. 1H NMR (300 MHz, CDCl3) δ 6.09 (s, 2H), 3.75-3.90 (m, 13H), 3.11 (t, J=5.1 Hz, 1H), 1.91 (t, J=5.8 Hz, 2H), 1.38 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 160.4, 158.8, 106.1, 90.6, 60.8, 55.8, 55.2,...

example 3

2-(4-(2-Methyl-2-(nitrosothio)propyl)piperazinyl)-2-oxoethyl 2-((2E)-3-(3,4-dimethoxyphenyl)prop-2-enoylamino)benzoate

[0477]

3a. 2,2-Dimethylthiirane

[0478] A mixture of 2,2-dimethyloxirane (25 g, 346 mmol), water (50 ml), and potassium thiocyanate (67 g, 692 mmol) was stirred at room temperature for 20 hours. The organic phase was removed, dried over Na2SO4, and filtered to give title compound (26.4 g, 87% yield). 1H NMR (300 MHz, CDCl3) δ 2.41(s, 2H), 1.62 (s, 6H).

3b. 2-Methyl-1-piperazinylpropane-2-thiol

[0479] A mixture of piperazine (44.7 g, 0.52 mol) and the product of Example 3a (15.2 g, 0.17 mmol) in toluene (70 mL) was heated at 80° C. for 6 hours. The reaction mixture was cooled, poured into water and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and the solvent evaporated to give the title compound (30.5 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ 2.80-2.90 (m, 4H), 2.50-2.60 (m, 4H), 2.35 (s, 2H), 1.52 (br s, 1H), 1.29 (s, 6H).

3c. 2-(4-(2-...

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Abstract

The invention describes novel nitrosated and / or nitrosylated compounds of the invention, and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and / or nitrosylated compound of the invention, and, optionally, at least one nitric oxide donor compound and / or at least one therapeutic agent. The invention also provides novel compositions comprising at least one compound of the invention, that is optionally nitrosated and / or nitrosylated, and at least one nitric oxide donor compound and / or at least one therapeutic agent. The compounds and compositions of the invention can also be bound to a matrix. The invention also provides methods for treating cardiovascular diseases, for inhibiting platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device, for treating pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune, inflammatory, proliferative, hyperproliferative or vascular diseases; for reducing scar tissue or for inhibiting wound contraction, particularly the prophylactic and / or therapeutic treatment of restenosis by administering at least one compound of the invention that is optionally nitrosated and / or nitrosylated, in combination with nitric oxide donors that are capable of releasing nitric oxide or indirectly delivering or transferring nitric oxide to targeted sites under physiological conditions. The compounds of the invention are preferably estradiol compounds, troglitazone compounds, tranilast compounds, retinoic acid compounds, resveratol compounds, myophenolic acid compounds, acid compounds, anthracenone compounds and trapidil compounds.

Description

RELATED APPLICATIONS [0001] This application claims priority under 35 USC § 120 to PCT / US04 / 007943 filed Mar. 15, 2004, which claims priority under 35 USC § 119 to U.S. Application No. 60 / 453,963 filed Mar. 13, 2003 and U.S. Application No. 60 / 482,134 filed Jun. 25, 2003.FIELD OF THE INVENTION [0002] The invention describes novel nitrosated and / or nitrosylated compounds of the invention, and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and / or nitrosylated compound of the invention, and, optionally, at least one nitric oxide donor compound and / or at least one therapeutic agent. The invention also provides novel compositions comprising at least one compound of the invention, that is optionally nitrosated and / or nitrosylated, and at least one nitric oxide donor compound and / or at least one therapeutic agent. The compounds and compositions of the invention can also be bound to a matrix. The invention also provides methods for treat...

Claims

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Application Information

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IPC IPC(8): A61K31/56A61K31/21A61KA61K31/58C07J1/00C07J17/00C07J43/00
CPCC07J1/00C07J17/00C07J43/003C07J41/0044C07J43/00C07J31/006
Inventor EARL, RICHARD A.GARVEY, DAVID S.GASTON, RICKY D.LIN, CHIA-ENRANATUNGE, RAMANI R.RICHARDSON, STEWART K.STEVENSON, CHERI A.
Owner NICOX SA
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